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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [Cut&Run]

ABSTRACT: The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173753 | GEO | 2022/12/14

REPOSITORIES: GEO

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Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia [RNA-seq]

Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.

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Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We apply a novel computational deep learning strategy to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.

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mCG-PML-RARA alters multipotent hematopoiesis.

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mCG-PML-RARA alters multipotent hematopoiesis.

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Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. Bone marrow from individual mice expressing PML-RARA from the murine Ctg locus (mCG-PR) and littermate controls was harvested from both femurs and tibia. Standard cell lysis was performed, and total RNA was extracted from the cells and analyzed using the Affymetrix Mouse Exon 1.0 ST platform.

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